The invention relates to opioid receptor binding compounds containing carboxamides, formamides, thiocarboxamides and hydroxyamidines. The compounds are useful as analgesics, anesthetics, anti-diarrheal agents, anti-retroviral agents, anticonvulsants, antitussives, anti-cocaine, and anti-addiction medications.
Opiates have been the subject of intense research since the isolation of morphine in 1805, and thousands of compounds having opiate or opiate-like activity have been identified. Many opioid receptor-interactive compounds including those used for producing analgesia (e.g., morphine) and those used for treating drug addiction (e.g., naltrexone and cyclazocine) in humans have limited utility due to poor oral bioavailability and a very rapid clearance rate from the body. This has been shown in many instances to be due to the presence of the 8-hydroxyl group (OH) of 2,6-methano-3-benzazocines, also known as benzomorphans [(e.g., cyclazocine and EKC (ethylketocyclazocine)] and the corresponding 3-OH group in morphinanes (e.g., morphine). 
The high polarity of these hydroxyl groups retards oral absorption of the parent molecules. Furthermore, the 8-(or 3-)OH group is prone to sulfonation and glucuronidation (Phase II metabolism), both of which facilitate rapid excretion of the active compounds, leading to disadvantageously short half-lives for the active compounds. Unfortunately, the uniform experience in the art of the past seventy years has been that removal or replacement of the 8-(or 3-)OH group has lead to pharmacologically inactive compounds.
We have now found that the 8-(or 3-)hydroxyl group may be replaced by a number of small, polar, neutral residues, such as carboxamide, thiocarboxamide, hydroxyamidine and formamide groups. Not only do the benzomorphan, morphinan carboxamides have unexpectedly high affinity for opioid receptors, compounds containing these groups in place of OH are far less susceptible to Phase II metabolism and are generally more orally bioavailable. The compounds of the invention are therefore useful as analgesics, anesthetics, anti-pruritics, anti-diarrheal agents, anticonvulsants, antitussives, anorexics and as treatments for hyperalgesia, drug addiction, respiratory depression, dyskinesia, pain (including neuropathic pain), irritable bowel syndrome and gastrointestinal motility disorders. Drug addiction, as used herein, includes alcohol and nicotine addiction. There is evidence in the literature that the compounds may also be useful as anti-retroviral agents, immunosuppressants and antiinflammatories and for reducing ischemic damage (and cardioprotection), for improving learning and memory, and for treating urinary incontinence.
In one aspect, the invention relates to 2,6-methano-3-benzazocine-8-carboxamides and 2,6-methano-3-benzazocine-8-carboxylate esters of formula: 
wherein
A is chosen from xe2x80x94CH2xe2x80x94Z, xe2x80x94CN, xe2x80x94NHSO2-(loweralkyl), 
Q is chosen from O, S and NR17;
Y is chosen from O, S, NR17 and NOH;
Z is chosen from OH, SH, CN and NH2;
R1 is chosen from hydrogen, lower alkoxy, phenyl and xe2x80x94NHR8;
R2 and R2a are both hydrogen or taken together R2 and R2a are xe2x95x90O;
R3 is chosen from hydrogen, lower alkyl, alkenyl, aryl, heterocyclyl, benzyl and hydroxyalkyl;
R4 is chosen from hydrogen, hydroxy, amino, lower alkoxy, C1-C20 alkyl and C1-C20 alkyl substituted with hydroxy or carbonyl;
R5 is lower alkyl;
R6 is lower alkyl;
R7 is chosen from hydrogen and hydroxy; or
together R4, R5, R6 and R7 may form from one to three rings, said rings having optional additional substitution;
R8 is chosen from hydrogen, xe2x80x94OH, xe2x80x94NH2 and xe2x80x94CH2R15;
R15 is chosen from hydrogen, alkyl, aryl, substituted aryl and alkyl substituted with alkoxy, amino, alkylamino or dialkylamino;
R16 is chosen from hydrogen and NH2; and
R17 is chosen from hydrogen, alkyl, aryl and benzyl;
with the provisos that, (1) when R2 and R2a are hydrogen, R3 is hydrogen or cyclopropyl, R4 is hydroxy, and together R5, R6 and R7 form two rings substituted with a spirodioxolane, A cannot be xe2x80x94COOCH3 or NHSO2CH3; (2) when R2 and R2a are hydrogen, R3 is hydrogen or cyclopropyl, R4 is hydroxy, and together R5, R6 and R7 form the ring system of oxymorphone and naltrexone, A cannot be NHSO2CH3; (3) when R2, R2a, R4 and R7 are hydrogen, R3 is cyclopropyl and R5 and R6 are methyl, A cannot be xe2x80x94NHC(O)H. The explicit provisos exclude oxymorphone and naltrexone-3-sulfonamides, which were disclosed as having no activity in vitro or in vivo [McCurdy et al. Org. Lett. 2, 819-821 (2000)]; and cyclazocine formamide, which was disclosed as an intermediate in a synthesis in U.S. Pat. Nos. 3,957,793; 4,032,529 and 4,205,171. Additionally, when A is xe2x80x94CN, R7 must be hydroxyl. When R4, R5, R6 and R7 form from one to three rings, it is preferred that none of the rings formed by R4, R5, R6 and R7 is aryl or heteroaryl.
Subclasses of the foregoing structure include:
II. 2,6-methano-3-benzazocines of the structure shown above, in which R4, R5, R6 and R7 do not form additional rings;
III. morphinans in which R5 and R6 form one ring: 
IV. morphinans in which R5, R6 and R7 form two rings: 
and
V. morphinans wherein R4 and R11 form an additional sixth ring, which may be saturated or unsaturated (but not fully aromatic): 
In addition to the major subclasses, there are compounds such as 
which the person of skill recognizes as closely related to the major subclasses, but which defy easy description in a common Markush structure.
In another aspect, the invention relates to a method for preparing a second compound that interacts with an opioid receptor when a first compound that interacts with an opioid receptor is known. When the first compound contains a phenolic hydroxyl, the method comprises converting the phenolic hydroxyl to a residue chosen from the group described as the variable A above.
In another aspect, the invention relates to a method for decreasing the rate of metabolism of a compound that interacts at an opioid receptor. When the first compound contains a phenolic hydroxyl, the method comprises converting the phenolic hydroxyl to a residue chosen from the group described as the variable A above.
In another aspect, the invention relates to methods for inhibiting, eliciting or enhancing responses mediated by an opioid receptor comprising:
(a) providing a first compound that inhibits, elicits or enhances an opioid receptor response;
(b) preparing a second compound that interacts with an opioid receptor by converting a phenolic hydroxyl group on the first compound to a residue described as A above; and
(c) bringing the second compound into contact with the opioid receptor.
In another aspect, the invention relates to a method for treating a disease by altering a response mediated by an opioid receptor. The method comprises bringing into contact with the opioid receptor a compound having the formula 
wherein B represents the appropriate residue of a known compound of formula 
and the known compound of that formula alters a response mediated by an opioid receptor.
In another aspect, the invention relates to processes for converting opioid-binding phenols or phenols on a benzomorphan or morphinan to a carboxamide. The carboxamide conversion processes comprise either:
(a) reacting the phenol with a reagent to convert it to a group displaceable by CNxe2x8ax96;
(b) reacting that group with Zn(CN)2 in the presence of a Pd(0) catalyst to provide a nitrile; and
(c) hydrolyzing the nitrile to a carboxamide; or:
(a) reacting the phenol with a reagent to convert the phenol to a triflate;
(b) reacting the triflate with carbon monoxide and ammonia in the presence of a Pd(II) salt and a Pd(0) catalyst to provide a carboxamide; or
(a) reacting the phenol with a reagent to convert the phenol to a triflate;
(b) reacting the triflate with carbon monoxide and hexamethyldisilazane in the presence of a Pd(II) salt and a Pd(0) catalyst to provide a silylated carboxamide precursor; and
(c) hydrolyzing the silylated carboxamide precursor to provide a carboxamide.
Similar processes convert phenols to amidines and thioamides by reacting the foregoing nitrile with hydroxylamine to produce a hydroxyamidine or reacting the foregoing carboxamide with a pentavalent phosphorus-sulfur reagent to produce a thioamide. For the purpose of the invention an xe2x80x9copioid-binding phenolxe2x80x9d is one that exhibits binding at an opioid receptor below 25 nM.